Knowledge concerning the regulatory control of mesotelencephalic dopamine (DA) neurons is crucial for obtaining a better understanding of their role in both normal and abnormal behavior, and the mechanisms by which antipsychotic drugs (APD) partially ameliorate psychotic symptoms. DA depletion, as well as DA excess, can produce profound deficits in prefrontal cortex (PFC) function. This proposal is directed at studying the regulatory control, adaptation, and pharmacology PFC DA system under normal, hypoactive and hyperactive states. The hypoactive state will be induced by subchronic treatment with phencyclidine (PCP) and/or delta9-tetrahydrocannabinol (ThC). Long-term abuse of PCP or marijuana is linked with deficits of frontal lobe function providing relevance for our findings in animals. Our studies with PCP(rat and monkey) and THC (rat) have demonstrated that subchronic treatment with these two different classes of psychotomimetic agents produce a decrease in DA release and turnover in the PFC and impair spatial working memory. The atypical APD, clozapine, is effective in reversing the cognitive impairment and normalizing PFC DA turnover in the PCP dysregulated state. This proposal will study the regulatory control of PFC DA in the PCP dysfunctional state in the rat and examine the receptor mechanisms involved in the clozapine reversal of the deficit. The ability of other atypical APD to reverse this PFC DA deficit and cognitive impairment will also be studied. Our rat data indicate that subchronic exposure to THC produces a prolonged dysregulation of PFC dopaminergic transmission and altered PFC dependent behavior. The neurochemical and anatomical specificity of this deficit, and its endurance and reversal by atypical APD, will be examined in both rat and monkey. Acute administration of THC in rats elicits a rapid increase in PFC DA turnover and release, and impairs PFC-dependent functions. These cognitive deficits can be reversed or prevented by drugs or conditions that attenuate the DA increase or block its action. Because of the considerable differences in the anatomy and regulatory control of cortica] DA systems between rodents and primates, the acute and chronic effects of THC on PFC DA function will be studied in the monkey. We will also determine if the pharmacological reversal of the THC-induced DA dysregulation and cognitive deficits observed in rodents is conserved in primates. The generation of critical neurochemical, behavioral and pharmacological data on 2 perturbed conditions of the PFC DA system in both rodents and primates may provide important new insights concerning the neural systems relevant to the PFC cognitive dysfunction in schizophrenia and their modulation by APD and other novel agents.